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ScienceWeek
NEUROSCIENCE: ON MEMORY AND THE CEREBELLUM
The following points are made by David J. Linden (Science 2003 301:1682):
1) The "holy grail" of memory researchers is to produce a comprehensive model of memory storage that flows from molecules to behavior with all of the intermediate steps defined. This level of understanding does not yet exist for any form of memory in any model organism.
2) Pioneering neuroscientists such as I.M. Sechenov (1829-1905), Santiago Ramon y Cajal (1852-1934), and Donald O. Hebb (1904-1985) hypothesized that memory could be stored by experience-dependent changes in synaptic strength. This idea gained momentum in 1973, when Terje Lomo and Tim Bliss discovered that brief high-frequency stimulation of excitatory synapses in the hippocampus of the brain could produce a long-lasting increase in the strength of synaptic transmission, a phenomenon called "long-term synaptic potentiation" (LTP). Some years later, a use-dependent synaptic weakening called "long-term synaptic depression" (LTD) was also found in the hippocampus. The idea that LTP and LTD could underlie memory storage became popular, in part, because damage to the hippocampus was known to produce impairments in memory for facts and events, so-called declarative memory. As the molecular underpinnings of hippocampal LTP and LTD became more defined, neuroscientists sought to understand memory storage in terms of these changes in synaptic strength.
3) Realization of this promise for the hippocampal system has not been straightforward. The current state of the art among aficionados of hippocampal memory is to inject a drug or introduce a mutation in mice that will interfere with LTP or LTD. Sometimes this will produce a deficit in a declarative memory task (2), but this approach has yielded little understanding of the intermediate processes by which LTP and LTD might change hippocampal circuit and regional function to constitute a behavioral memory trace.
4) Fortunately, this approach is somewhat more tractable for some simple, nondeclarative forms of memory such as associative eyelid conditioning. In this task, a weak periorbital shock (the unconditioned stimulus, US) is delivered to the eye, eliciting a reflexive blink (the unconditioned response, UR). When a neutral conditioned stimulus (CS) such as a tone is repeatedly paired with a periorbital shock so that the two terminate simultaneously, the animal learns to blink its eye in a carefully timed manner (the conditioned response, CR) such that the eyelid is lowered when the shock arrives. This simple form of motor learning is blocked if the cerebellum is damaged or temporarily inactivated with drugs during training. Furthermore, in well-trained animals, populations of cells in a region called the deep cerebellar nuclei begin to fire during the interval between CS onset and US onset. This firing is predictive of the performance of the CR, suggesting that the memory trace for associative eyelid conditioning is expressed in the firing rate and pattern of deep nuclear neurons. Of importance is that during training, artificial electrical stimulation of cerebellar mossy and climbing fibers can substitute for the tone CS and shock US, respectively. These observations constrain the potential site of the memory trace: It must be in a location where the streams of CS and US information converge, and it must result in a carefully timed increase in firing of the deep cerebellar nuclei.
5) One favored hypothesis is that simultaneous activation of US-encoding climbing fibers and a CS-encoding mossy fiber-parallel fiber disynaptic relay results in LTD of excitatory parallel fiber-Purkinje cell synapses (3-5), particularly those that are active shortly before the US signal arrives. This results in reduced Purkinje cell firing, which attenuates inhibitory drive from the Purkinje cell to the deep cerebellar nuclei. This drives the increase in deep nuclear activity that underlies the timed eyeblink CR. Thus, for associative eyelid conditioning, an actual circuit-based model exists to relate a synaptic phenomenon (parallel fiber LTD) to a behavior (acquisition of the CR).(1)
References (abridged):
1. S. K. E. Koekkoek et al., Science 301, 1736 (2003)
2. S. J. Martin, R. G. Morris, Hippocampus 12, 609 (2002)
3. J. S. Albus, Math. Biosci. 10, 25 (1971)
4. M. Ito, Annu. Rev. Neurosci. 12, 85 (1989)
5. R. F. Thompson, D. J. Krupa, Annu. Rev. Neurosci. 17, 519 (1994)
Science http://www.sciencemag.org
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ON THE NEUROBIOLOGY OF LEARNING AND MEMORY
The following points are made by H. Okano et al (Proc. Nat. Acad. Sci. 2000 97:12403):
1) The authors state they define memory as a behavioral change caused by an experience, and they define learning as a process for acquiring memory. According to these definitions, there are different kinds of memory. Some memories, such as those concerning events and facts, are available to our consciousness; this type of memory is called "declarative memory". However, another type of memory, called "procedural memory", is not available to consciousness. This is the memory that is needed, for example, to use a previously learned skill. We can improve our skills through practice: with training, the ability to play tennis, for example, will improve. Declarative memory and procedural memory are independent: there are patients with impaired declarative memory whose procedural memory is completely normal. Because of this fact, current researchers believe there must be separate mechanisms for each type of memory, and that these separate mechanisms probably also require separate brain areas as well.
2) The *cerebrum and *hippocampus are considered important for declarative memory, and the *cerebellum is considered important for procedural memory. The current belief is that memory requires alterations in the brain. The most popular candidate site for memory storage is the *synapse, where nerve cells communicate with each other. A change in the transmission efficacy at the synapse (called "synaptic plasticity") has been considered to be the cause of memory, and a particular pattern of synaptic usage or stimulation (conditioning stimulation) is believed to induce synaptic plasticity. Many questions remain to be answered, such as how synaptic plasticity is induced and how synaptic plasticity is implicated in learning and memory.
3) One current frontier in the study of synaptic plasticity is the attempt to clarify the role of plasticity in learning and memory. The strategy has been to examine the correlation between synaptic plasticity and learning by inhibiting the plasticity in a living animal. To do this, investigators have used inhibitors for certain molecules that are apparently required for synaptic plasticity. Another set of useful tools involves genetically engineered mutant mice, such as "knockout" and transgenic mice. A "knockout" mouse is a mutant mouse that is deficient in a specific native molecule. By using mutant mice, the relationship between synaptic plasticity and learning ability has been examined in detail.
Proc. Nat. Acad. Sci. http://www.pnas.org
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Notes:
cerebrum: What is called the "cerebrum" is the bulk of brain as seen by the naked eye, the "great ravelled knot" that sits on top of the phylogenetically older parts (brainstem and midbrain) of the whole brain. The surface of the cerebrum, an enormously extended surface because of the many deep folds of the cerebrum, is a thin sheet called the "cerebral cortex" (cortex = rind or bark).
hippocampus: A region of the cerebral cortex in the *medial part of the temporal lobe. In humans, among other functions, the hippocampus is apparently involved in short-term memory, and analysis of the neurological correlates of learning behavior in animals indicates that the hippocampus is also involved in memory in other species.
cerebellum: The human cerebellum is about the size of a large apple, is placed at the lower back of the head under the optic lobes of the cerebrum, and is apparently involved in the input-output control of automatic sensorimotor functions. If you are sitting at your breakfast table, holding a newspaper in one hand, and using the other hand to routinely and repetitively dip a spoon into cold cereal and bring the cold cereal to your mouth while you read the newspaper, it is the cerebellum which is governing the automatic feeding movements while your cerebral cortex processes the information that you read.
synapse: In general, nerve cells have a single long extension (the "axon") that propagates the electrical output (the action potential) of the cell. The term "synapse" refers to the junction between the terminal of a neuron's axon and another neuron. When studying the synapse, the first neuron is called the "presynaptic" neuron, and the second neuron is called the "postsynaptic" neuron.
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ON THE CEREBELLUM AND CLASSICAL EYELID CONDITIONING:
The following points are made by J.E. Steinmetz et al (J. Neurosci 1992 12:4403):
1) Over the past 10 years, a number of laboratories have reported that classically conditioned skeletal muscle responses, such as conditioned nictitating membrane/eyelid responses, are critically dependent on activity in the cerebellum. For example, unilateral lesions of the cerebellar interpositus nucleus have been shown to prevent acquisition and abolish retention of the conditioned eyelid response on the side ipsilateral to the lesions without affecting conditioned responding (CR) on the contralateral side. Also, recording studies involving the interpositus nucleus have consistently revealed patterns of neuronal discharge that predict execution of the CR. The lesion and recording studies have generally been cited as evidence that plasticity in the cerebellum is critically involved in the learning and memory of classically conditioned responses.
2) This interpretation was recently challenged by Welsh and Harvey (1989), who claimed that cerebellar lesions simply produced a performance deficit and speculated that the role of the cerebellum was not in learning and memory processes associated with the CR but only in performance of the eye blink response.
3) The authors (Steinmetz et al) present three experiments that provide additional strong evidence for a critical role of the cerebellum in the learning and memory of the Pavlovian CR. These experiments include (1) demonstrations of complete and permanent CR abolition after appropriate interpositus lesions, (2) a failure to find systematic or persisting decrements in the unconditioned response amplitude (i.e., the eye blink reflex) after appropriate interpositus lesion, and (3) observations of differential effects on the CR and unconditioned response after lesions were placed in populations of motoneurons responsible for executing the eye blink response. The authors discuss these data in the context of performance versus learning issues. The authors suggest their evidence rules out the possibility that interpositus lesion abolition of the eye blink CR is simply due to lesion effects on performance.
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